Comprehensive characterization of the Published Kinase Inhibitor Set

DOI: 10.1038/nbt.3374
PMID: 26501955

Authors: Jonathan M Elkins (University of Oxford) , Vita Fedele (University of Oxford) , Marta Szklarz (University of Oxford) , Kamal R Abdul Azeez (University of Oxford) , Eidarus Salah (University of Oxford) , Jowita Mikolajczyk (Nanosyn, Inc) , Sergei Romanov (Nanosyn, Inc) , Nikolai Sepetov (Nanosyn, Inc) , Xi-Ping Huang (The University of North Carolina Chapel Hill School of Medicine) , Bryan L Roth (The University of North Carolina Chapel Hill School of Medicine) , Ayman Al Haj Zen (University of Oxford) , Denis Fourches (The University of North Carolina Chapel Hill School of Medicine) , Eugene Muratov (The University of North Carolina Chapel Hill School of Medicine) , Alex Tropsha (The University of North Carolina Chapel Hill School of Medicine) , Joel Morris (National Cancer Institute) , Beverly A Teicher (National Cancer Institute) , Mark Kunkel (National Cancer Institute) , David H Drewry (GlaxoSmithKline) , William J Zuercher (GlaxoSmithKline) , Stefan Knapp (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature Biotechnology

State: Published (Approved)
Published: October 2015

Abstract: Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein–coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.

Journal Keywords: Chemical Tools; Screening; Target Validation; X-Ray Crystallography

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 23/11/2015 10:53

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)